The<i>Rpe65<sup>rd12</sup></i>Allele Exerts a Semidominant Negative Effect on Vision in Mice

Wright, Charles B.; Chrenek, Micah A; Feng, Wei; Getz, Shannon; Duncan, Todd; Pardue, Machelle T.; Feng, Yue; Redmond, T. Michael; Boatright, Jeffrey H; Nickerson, John M.

doi:10.1167/iovs.13-13574

Cited by 12 publications

(13 citation statements)

References 71 publications

(108 reference statements)

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“…Mutation of genes involved in the visual cycle pathway cause PR degeneration, in most instances with a moderate to slow progression depending on the allele and the genetic background. Most Rpe65 mutant alleles show moderately slow PR cell loss (D 50 = 7-11 months) [284][285][286][287][288]. Allelic effects are observed in models bearing missense mutations, Rpe65 tm1Lrcb [289] or Rpe65 tm1.1Kpal [290], which cause slower progression than observed in Rpe65 tm1Tmr knockout mice [285][286][287][288].…”

Section: Category 04: Visual Cycle and Retinoidsmentioning

confidence: 99%

Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss

Collin

Gogna

Chang

et al. 2020

Cells

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Inherited retinal degeneration (RD) leads to the impairment or loss of vision in millions of individuals worldwide, most frequently due to the loss of photoreceptor (PR) cells. Animal models, particularly the laboratory mouse, have been used to understand the pathogenic mechanisms that underlie PR cell loss and to explore therapies that may prevent, delay, or reverse RD. Here, we reviewed entries in the Mouse Genome Informatics and PubMed databases to compile a comprehensive list of monogenic mouse models in which PR cell loss is demonstrated. The progression of PR cell loss with postnatal age was documented in mutant alleles of genes grouped by biological function. As anticipated, a wide range in the onset and rate of cell loss was observed among the reported models. The analysis underscored relationships between RD genes and ciliary function, transcription-coupled DNA damage repair, and cellular chloride homeostasis. Comparing the mouse gene list to human RD genes identified in the RetNet database revealed that mouse models are available for 40% of the known human diseases, suggesting opportunities for future research. This work may provide insight into the molecular players and pathways through which PR degenerative disease occurs and may be useful for planning translational studies.

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Section: Category 04: Visual Cycle and Retinoidsmentioning

confidence: 99%

Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss

Collin

Gogna

Chang

et al. 2020

Cells

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“…Some examples of the terminology used in peer-reviewed literature from the last 10 years to describe the same head-turning movement using the same experimental set-up include optokinetic reflex (Barabas et al, 2011; Franco et al, 2009; Lu et al, 2010a; Zulliger et al, 2011), optokinetic response (Benkner et al, 2013; Della Santina et al, 2013; Ho et al, 2012; Joly et al, 2014; Lodha et al, 2010; Lu et al, 2010b; McGill et al, 2007; Prusky et al, 2006; Thompson et al, 2014; Tsai et al, 2014; Wang et al, 2010), optokinetic tracking (Della Santina et al, 2013; McGill et al, 2012a; McGill et al, 2012b; Volz et al, 2014; Wright et al, 2014; Wright et al, 2013), optokinetic nystagmus (Bricker-Anthony et al, 2014; Savigni et al, 2013; Selt et al, 2010), optomotor testing (Zhou et al, 2009), OMR (Abdeljalil et al, 2005; Kretschmer et al, 2013; Lund et al, 2006; Prusky et al, 2004; Puk et al, 2009; Rangarajan et al, 2011), optomotor reflex (Barabas et al, 2011; Barabas et al, 2013; Redfern et al, 2011), optomotor tracking (Burroughs et al, 2011; Douglas et al, 2005; Kaja et al, 2014), head-tracking reflex (Hoelter et al, 2008; Puk et al, 2008), reflexive head movements (Wang et al, 2010). Of the aforementioned terms, the optokinetic reflex/ optokinetic nystagmus should be used to describe eye-tracking, and the optokinetic response/ optokinetic tracking/ optomotor testing/ optomotor response/ optomotor reflex/ optomotor tracking/ head-tracking reflex/ reflexive head movements used to describe head-tracking.…”

Section: Behavioral Assays Measuring Deficits In Rodent Visual Promentioning

confidence: 99%

“…Implementations of this assay include either a motorized cylindrical drum which can be lined with various removable cards printed with alternating vertical black and white stripes arranged to produce a known frequency (Abdeljalil et al, 2005; Hoelter et al, 2008; Puk et al, 2008; Savigni et al, 2013; Thaung et al, 2002) or custom (Benkner et al, 2013; Kretschmer et al, 2013; Redfern et al, 2011; Thomas et al, 2010; Wang et al, 2010) and commercial computer-generated virtual cylinders, such as the popular OptoMotry system from Cerebral Mechanics (Barabas et al, 2013; Burroughs et al, 2011; Douglas et al, 2005; Franco et al, 2009; Ho et al, 2012; Joly et al, 2014; Lu et al, 2010a; Lu et al, 2010b; McGill et al, 2012a; McGill et al, 2007; McGill et al, 2012b; Prusky et al, 2004; Puk et al, 2009; Rangarajan et al, 2011; Thompson et al, 2014; Tsai et al, 2014; Volz et al, 2014; Wright et al, 2014; Wright et al, 2013; Zhou et al, 2009; Zulliger et al, 2011). The computer program displays rotating contrasting gratings at a constant speed in a virtual cylinder that also maintains a defined distance to the head of the animal (Burroughs et al, 2011; Douglas et al, 2005; Prusky et al, 2004).…”

Section: Behavioral Assays Measuring Deficits In Rodent Visual Promentioning

confidence: 99%

Psychophysical testing in rodent models of glaucomatous optic neuropathy

Grillo

Koulen

2015

Experimental Eye Research

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Processing of visual information begins in the retina, with photoreceptors converting light stimuli into neural signals. Ultimately, signals are transmitted to the brain through signaling networks formed by interneurons, namely bipolar, horizontal and amacrine cells providing input to retinal ganglion cells (RGCs), which form the optic nerve with their axons. As part of the chronic nature of glaucomatous optic neuropathy, the increasing and irreversible damage and ultimately loss of neurons, RGCs in particular, occurs following progressive damage to the optic nerve head (ONH), eventually resulting in visual impairment and visual field loss. There are two behavioral assays that are typically used to assess visual deficits in glaucoma rodent models, the visual water task and the optokinetic drum. The visual water task can assess an animal’s ability to distinguish grating patterns that are associated with an escape from water. The optokinetic drum relies on the optomotor response, a reflex turning of the head and neck in the direction of the visual stimuli, which usually consists of rotating black and white gratings. This reflex is a physiological response critical for keeping the image stable on the retina. Driven initially by the neuronal input from direction-selective RGCs, this reflex is comprised of a number of critical sensory and motor elements. In the presence of repeatable and defined stimuli, this reflex is extremely well suited to analyze subtle changes in the circuitry and performance of retinal neurons. Increasing the cycles of these alternating gratings per degree, or gradually reducing the contrast of the visual stimuli, threshold levels can be determined at which the animal is no longer tracking the stimuli, and thereby visual function of the animal can be determined non-invasively. Integrating these assays into an array of outcome measures that determine multiple aspects of visual function is a central goal in vision research and can be realized, for example, by the combination of measuring optomotor reflex function with electroretinograms (ERGs) and optical coherence tomography (OCT) of the retina. These structure-function correlations in vivo are urgently needed to identify disease mechanisms as potential new targets for drug development. Such a combination of the experimental assessment of the optokinetic reflex (OKN) or optomotor reflex (OMR) with other measures of retinal structure and function is especially valuable for research on GON. The chronic progression of the disease is characterized by a gradual decrease in function accompanied by a concomitant increase in structural damage to the retina, therefore the assessment of subtle changes is key to determining the success of novel intervention strategies.

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“…To investigate this possibility we used rd12 animals, which carry a mutation in the Rpe65 gene that disrupts recycling of the chromophore (Pang et al, 2005). Previous results based on optokinetic reflex revealed detectable responses below 0.2 cycles/degrees in adult animals aged between 9 and 18 weeks (Wright et al, 2014). We presented looming grating stimuli over a range of spatial frequencies (0.017-0.272 cpd) to an age-matched cohort (n = 7; 14.4±4.4sd weeks) of rd12 mice.…”

Section: Behavioural Responses In Mouse Models Of Retinal Degenerationmentioning

confidence: 95%

Measuring vision using innate behaviours in mice with intact and impaired retina function

Storchi

Rodgers

Gracey

et al. 2019

Preprint

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Measuring vision in rodents is a critical step for understanding vision, improving models of human disease, and developing therapies. Established behavioural tests for perceptual vision, such as the visual water task, rely on learning. The learning process, while effective for sighted animals, can be laborious and stressful in animals with impaired vision, requiring long periods of training. Current tests that that do not require training are based on sub-conscious, reflex responses (e.g. optokinetic nystagmus) that don't require involvement of visual cortex and higher order thalamic nuclei. A potential alternative for measuring vision relies on using visually guided innate defensive responses, such as escape or freeze, that involve cortical and thalamic circuits. In this study we address this possibility in mice with intact and degenerate retinas. We first develop automatic methods to detect behavioural responses based on high dimensional tracking and changepoint detection of behavioural time series. Using those methods, we show that visually guided innate responses can be elicited using parametisable stimuli, and applied to describing the limits of visual acuity in healthy animals and discriminating degrees of visual dysfunction in mouse models of retinal degeneration.

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TheRpe65^rd12Allele Exerts a Semidominant Negative Effect on Vision in Mice

Abstract: The rd12 lesion is in Rpe65. The rd12 mutant phenotype inherits in a semidominant manner. The effects of the mutant mRNA on visual function may result from inefficient binding to ribosomes for translation.

Cited by 12 publications

References 71 publications

Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss

Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss

Psychophysical testing in rodent models of glaucomatous optic neuropathy

Measuring vision using innate behaviours in mice with intact and impaired retina function

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TheRpe65rd12Allele Exerts a Semidominant Negative Effect on Vision in Mice

Abstract: The rd12 lesion is in Rpe65. The rd12 mutant phenotype inherits in a semidominant manner. The effects of the mutant mRNA on visual function may result from inefficient binding to ribosomes for translation.

Cited by 12 publications

References 71 publications

Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss

Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss

Psychophysical testing in rodent models of glaucomatous optic neuropathy

Measuring vision using innate behaviours in mice with intact and impaired retina function

Contact Info

Product

Resources

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TheRpe65^rd12Allele Exerts a Semidominant Negative Effect on Vision in Mice